• IMMUNE NETWORK
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• v.2 no.3
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• pp.137-141
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• 2002

Among the members of the inhibitor of apoptosis (IAP) protein family, only Livin and survivin have been reported to have variant forms. We have found a variant form of c-IAP2 through the interaction with the X protein of HBV using the yeast two-hybrid system. In contrast to the wild-type c-IAP2, the variant form has two stretches of sequence in the RING domain that are repeated in the C-terminus that would disrupt the RING domain. We demonstrate that the variant form has an inhibitory effect on TNF-mediated $NF-{\kappa}B$ activation unlike the wild-type c-IAP2, which increases TNFmediated $NF-{\kappa}B$ activation. These results suggest that this variant form has different activities from the wild-type and the RING domain may be involved in the regulation of TNF-induced $NF-{\kappa}B$ activation.

• BMB Reports
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• v.50 no.11
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• pp.584-589
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• 2017

Intercellular adhesion molecule-1 (ICAM-1), which is induced by tumor necrosis factor (TNF)-${\alpha}$, contributes to the entry of immune cells into the site of inflammation in the skin. Here, we show that protein tyrosine phosphatase non-receptor type 21 (PTPN21) negatively regulates ICAM-1 expression in human keratinocytes. PTPN21 expression was transiently induced after stimulation with TNF-${\alpha}$. When overexpressed, PTPN21 inhibited the expression of ICAM-1 in HaCaT cells but PTPN21 C1108S, a phosphatase activity-inactive mutant, failed to inhibit ICAM-1 expression. Nuclear factor-${\kappa}B$ (NF-${\kappa}B$), a key transcription factor of ICAM-1 gene expression, was inhibited by PTPN21, but not by PTPN21 C1108S. PTPN21 directly dephosphorylated phospho-inhibitor of ${\kappa}B$ ($I{\kappa}B$)-kinase ${\beta}$ ($IKK{\beta}$) at Ser177/181. This dephosphorylation led to the stabilization of $I{\kappa}B{\alpha}$ and inhibition of NF-${\kappa}B$ activity. Taken together, our results suggest that PTPN21 could be a valuable molecular target for regulation of inflammation in the skin by dephosphorylating p-$IKK{\beta}$ and inhibiting NF-${\kappa}B$ signaling.

• Biomolecules & Therapeutics
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• v.17 no.3
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• pp.219-240
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• 2009

Since NF-${\kappa}B$ has been identified as a transcription factor associated with immune cell activation, groups of researchers have dedicated to reveal detailed mechanisms of nuclear factor of ${\kappa}B$ (NF-${\kappa}B$) in inflammatory signaling for decades. The various molecular components of NF-${\kappa}B$ transcription factor pathway have been being evaluated as important therapeutic targets due to their roles in diverse human diseases including inflammation, cystic fibrosis, sepsis, rheumatoid arthritis, cancer, atherosclerosis, ischemic injury, myocardial infarction, osteoporosis, transplantation rejection, and neurodegeneration. With regards to new drugs directly or indirectly modulating the NF-${\kappa}B$ pathway, FDA recently approved a proteasome inhibitor bortezomib for the treatment of multiple myeloma. Many pharmaceutical companies have been trying to develop new drugs to inhibit various kinases in the NF-${\kappa}B$ signaling pathway for many therapeutic applications. However, a gene knock-out study for $IKK{\beta}$ in the NF-${\kappa}B$ pathway has given rise to controversies associated with efficacy as therapeutics. Mice lacking hepatocyte $IKK{\beta}$ accelerated cancer instead of preventing progress of cancer. However, it is clear that pharmacological inhibition of $IKK{\beta}$ appears to be beneficial to reduce HCC. This article will update issues of the NF-${\kappa}B$ pathway and inhibitors regulating this pathway.

• Biomolecules & Therapeutics
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• v.15 no.4
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• pp.218-223
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• 2007

T cell proliferation is a pivotal to an effective immune response. Cyclin-dependent kinase (cdk) inhibitor, $p27^{kip1}$ is degraded to initiate T cell expansion. In this study, we show that although the expression of $p27^{kip1}$ protein was down-regulated, that of $p21^{cip1}$, another cdk inhibitor, was up-regulated in $CD8^+$ T cells following in vitro stimulation. Ex vivo gB antigen-stimulation following HSV immunization increased $p21^{cip1}$ positive cells that co-expressed IFN-$\gamma$. Moreover, $p21^{cip1}$ was co-expressed with IFN-${\gamma}$ in E7 antigen-stimulated $CD8^+$ T cells, whereas $p27^{kip1}$ was not. Our findings imply a role of $p21^{cip1}$ proteins in antigen-induced effector $CD8^+$ T cells differentiation in vivo.

• IMMUNE NETWORK
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• v.12 no.4
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• pp.148-154
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• 2012

Previously, we have reported that high mobility group box 1 (HMGB1), a proinflammatory mediator in sepsis, is released via the IFN-${\beta}$-mediated JAK/STAT pathway. However, detailed mechanisms are still unclear. In this study, we dissected upstream signaling pathways of HMGB1 release using various molecular biology methods. Here, we found that calcium/calmodulin-dependent protein kinase (CaM kinase, CaMK) is involved in HMGB1 release by regulating IFN-${\beta}$ production. CaMK inhibitor, STO609, treatment inhibits LPS-induced IFN-${\beta}$ production, which is correlated with the phosphorylation of interferon regulatory factor 3 (IRF3). Additionally, we show that CaMK-I plays a major role in IFN-${\beta}$ production although other CaMK members also seem to contribute to this event. Furthermore, the CaMK inhibitor treatment reduced IFN-${\beta}$ production in a murine endotoxemia. Our results suggest CaMKs contribute to HMGB1 release by enhancing IFN-${\beta}$ production in sepsis.

• Biomedical Science Letters
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• v.25 no.4
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• pp.293-301
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• 2019

Combination chemotherapy is more effective than mono-chemotherapy and is widely used in clinical practice for enhanced cancer treatment. In this study, we investigated the potential synergistic effects of acetaminophen, a common component in many cold medicines, and romidepsin, a histone deacetylase (HDAC) inhibitor, in the A549 non-small cell lung cancer (NSCLC) cell line. The combination of acetaminophen and romidepsin also exerted significant cytotoxicity and apoptosis induced by activation of caspase-3 on tumor cells in vitro. Moreover, combination therapy significantly induced increased production of chemokines that stimulate migration of activated T-cells into tumor cells. This mechanism can lead to active T-cell mediated anti-tumor immunity in addition to the direct cytotoxic chemotherapeutic effect. Activated T-cells led to enhanced cytotoxicity in drug-treated A549 cells through interaction with tumor cells. These results suggested that the interaction between the two drugs is synergistic and significant. In conclusion, our data showed that the use of romidepsin and low concentrations acetaminophen could induce effective anti-tumor effects via enhanced tumor immune and direct cytotoxic chemotherapeutic responses. The combination of acetaminophen with romidepsin should be considered as a promising strategy for the treatment of lung cancer.

• Journal of the Korean Medical Association
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• v.61 no.11
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• pp.662-669
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• 2018

The cutaneous melanoma has been regarded as rare disease entity in Korea for long time but it shows a silent growth recently. Furthermore the management of cutaneous melanoma including staging system, surgical principle, sentinel lymph node biopsy and subsequent complete node dissection and, most importantly, immunotherapy and target therapy against cutaneous melanoma recently. The incidence of cutaneous melanoma is steadily increasing in Korea but its increase is rapid recent 2 decades to 4.3 times and should be greater soon according to the steeper increase of life expectancy. New staging system proposed by American Joint Committee on Cancer (2017) includes changes in individual TNM category and stage groups, particularly from a prognostic viewpoint. Dermoscopy has been successfully introduced in the differential diagnosis of pigmented skin lesion focusing on cutaneous melanoma by non-invasive simple diagnostic tool. Sentinel lymph node biopsy was a issue of long debate whether survival benefit is real or not. Temporary conclusion about this question is reached after two large scale studies and immediate complete node dissection should be performed in a certain situations. Most important change is drug therapy focusing on immunotherapy and target therapy. Braf- and MEK-inhibitor, immune checkpoint inhibitor and PD-1 blocker has been proved to be effective as a sole or combination regimen against advanced and/or high-risk adjuvant setting of cutaneous melanoma. In conclusion, these remarkable changes will be reviewed shortly here.

• Biomedical Science Letters
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• v.28 no.4
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• pp.247-259
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• 2022

Immunotherapy, which uses an immune mechanism in the body, has received considerable attention for cancer treatment. Suberoylanilide hydroxamic acid (SAHA), also known as a histone deacetylase inhibitor (HDACi), is used as a cancer treatment to induce active immunity by increasing the expression of T cell-induced chemokines. However, this SAHA treatment has the disadvantage of causing PD-L1 overexpression in tumor cells. In this study, we prevented PD-L1 overexpression by blocking the PD-1/PD-L1 pathway using PD-L1 siRNA. We designed two types of liposomes, the neutral lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholin (POPC) for SAHA, and 1,2-dioleoyl-3-trimethylammoniumpropane (DOTAP) for siRNA. To effectively target PD-L1 in cancer cells, we conjugated PD-L1 antibody with liposomes containing SAHA or PD-L1 siRNA. These immunoliposomes were also evaluated for cytotoxicity, gene silencing, and T-cell-induced chemokine expression in human non-small cell lung cancer A549 cells. It was confirmed that the combination of the two immunoliposomes increased the cancer cell suppression efficacy through Jurkat T cell induction more than twice compared to SAHA alone treatment. In conclusion, this combination of immunoliposomes containing a drug and nucleic acid has promising therapeutic potential for non-small-cell lung carcinoma (NSCLC).

• Journal of Digestive Cancer Research
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• v.6 no.1
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• pp.6-10
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• 2018

The importance of signal transducer and activator of transcription 3 (STAT3) signaling in gastric carcinogenesis was firmly evaluated in the previous studies. Fully activated STAT3 induces various target genes involving tumor invasion and epithelial-mesenchymal transition (EMT), and mediates interaction between cancer cells and microenvironmental immune cells. Thus, suppression of STAT3 activity is an important issue for inhibition of gastric carcinogenesis and invasion. Unfortunately, data from clinical studies of direct inhibitor targeting STAT3 have been disappointing. SH2-containing protein tyrosine phosphatase 1 (SHP-1) effectively dephosphorylates and inhibits STAT3 activity, which has not been extensively studied gastric cancer research field. However, by summarizing recent data, it is evident that protein and gene expression of SHP-1 are minimal in gastric cancer cells, and induction of SHP-1 effectively downregulates phosphorylated STAT3 and inhibits cellular invasion in gastric cancer cells. Several SHP-1 inducers have been investigated in the experimental studies, including proton pump inhibitor, arsenic trioxide, and other natural compounds. Taken together, we suggest that modulation of SHP-1/STAT3 signaling axis may present a new way for treatment of gastric cancer, and development of effective SHP-1 inducer may be an important task in the future search field of gastric cancer.

• BMB Reports
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• v.36 no.1
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• pp.128-137
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• 2003

Matrix metalloproteinases (MMPs), zinc dependent proteolytic enzymes, cleave extracellular matrix (ECM: collagen, laminin, firbronectin, etc) as well as non-matrix substrates (growth factors, cell surface receptors, etc). The deregulation of MMPs is involved in many diseases, such as tumor metastasis, rheumatoid arthritis, and periodontal disease. Metastasis is the major cause of death among cancer patients. In this review, we will focus on the roles of MMPs in tumor metastasis. The process of metastasis involves a cascade of linked, sequential steps that involve multiple host-tumor interactions. Specifically, MMPs are involved in many steps of tumor metastasis. These include tumor invasion, migration, host immune escape, extravasation, angiogenesis, and tumor growth. Therefore, without MMPs, the tumor cell cannot perform successful metastasis. The activities of MMPs are tightly regulated at the gene transcription levels, zymogen activation by proteolysis, and inhibition of active forms by endogenous inhibitors, tissue inhibitor of metalloproteinase (TIMP), and RECK. The detailed regulations of MMPs are described in this review.